Tachyphylaxis/tolerance to antidepressants in treatment of dysthymia: Results of a retrospective naturalistic chart review studypcn_

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1 Psychiatry and Clinical Neurosciences 2011; 65: doi: /j x Regular Article Tachyphylaxis/tolerance to antidepressants in treatment of dysthymia: Results of a retrospective naturalistic chart review studypcn_ Gregory Katz, MD* The Jerusalem Mental Health Centre Kfar Shaul Psychiatric Hospital, Hadassa Medical School, Hebrew University, Jerusalem, Israel Aim: The main goals of this chart-review study were to examine the rate of during treatment of dysthymia with antidepressants, to compare the incidence of tolerance during trials of selective serotonin reuptake inhibitors (SSRI) and non-ssri and to give descriptive analysis of the cases of. Methods: The retrospective naturalistic chart review study included 52 cases of successfully treated (with different antidepressants) patients suffering from dysthymia. The overall number of the cases of tolerance to antidepressants were registered as well as the rate of these phenomena in the groups treated with SSRI and non-ssri. Results: The cases of tolerance/ were observed in 12 patients (23% of patients) and in 13 trials (22.4% of trials). All cases of tolerance occurred during monotherapy. No cases of were observed in the non-ssri group while in the SSRI group, tolerance at some stage of the treatment was detected in 41.9% of the successful cases (P < 0.001). Conclusion: During the treatment of dysthymia with antidepressants in the SSRI group, / tolerance might be observed in a relatively in high proportion of cases. Key words: antidepressants, dysthymia,, tolerance. THE PHARMACOLOGIC TERM is defined as an appearance of progressive decrease in response to a given dose after repetitive administration of a pharmacologically or physiologically active substance. 1 In some studies, (or poop-out ) is defined as a relapse or recurrence of an episode of major depression after full recovery from a major depressive episode despite continued treatment with a previously effective antidepressant; 2 other studies characterize the phenomenon as a return of depressed mood, apathy or decreased motivation (described by patients as the blahs ), fatigue, *Correspondence: Gregory Katz, MD, The Jerusalem Mental Health Centre Kfar Shaul Psychiatric Hospital, Hadassa Medical School- Hebrew University, Givat Shaul Beith 91060, Jerusalem 91060, Israel. ngkatz@012.net.il Received 4 November 2010; revised 25 April 2011; accepted 17 May dullness in cognitive function, sleep disturbance, weight gain, and sexual dysfunction. 3 Patients frequently report the some deterioration they felt after initially achieving remission on the antidepressant, but not as bad as they felt before treatment when they were in an episode of major depression. 4 Although in most clinical studies the term is used, the term tolerance could be more correct from a pharmacologic point of view. 5 While the term antidepressant stresses mostly the possibility of habituation/sensitization mechanisms, the term tolerance is much more comprehensive and includes the mechanisms of pharmacodynamic tolerance, pharmacokinetic tolerance, increase in disease severity, change in disease pathogenesis, depleted effector substance, prominent increase of drug serum level and existence of detrimental metabolite. 6 In the current report the terms and tolerance have been used interchangeably. 499

2 500 G. Katz Psychiatry and Clinical Neurosciences 2011; 65: Over a 2-week period, the Rothschild Scale for Antidepressant Tachyphylaxis (RSAT) 4 was used to assess disturbances (energy level, motivation and interest, cognitive functioning, sleep, and sexual functioning) in patients on antidepressants who do not currently fulfill the criteria for an episode of major depression and had a previous good response to antidepressant therapy. The frequency of antidepressant tolerance is still unknown and is reportedly from 9% to 33% of patients in published trials. 6 Some data suggest that rates of are significantly lower with the dual reuptake inhibitors and tricyclic antidepressants (TCA) compared to rates of with SSRI, 7 but the issue is still far from clear. Most of the studies concerning antidepressants were performed during treatment of major depressive disorder or bipolar depression. Very little is known about the possible tolerance in treatment of other depressive conditions, including dysthymia. According to DSM-IV-R 8 for diagnosis of dysthymia, at least two of the following symptoms are compulsory: (i) change in appetite (increase or decrease); (ii) change in sleep pattern (increase or decrease); (iii) fatigue or low energy; (iv) low selfesteem; (v) decrease in concentration or inductiveness; and (vi) feelings of hopelessness. The symptoms must be presented for at least a 2-year period for adults and for 1 year for adolescents. While brief periods of normal mood can be observed during this 2-year period, the clinical signs are never absent for more than 2 consecutive months. Dysthymic disorder is described as a semichronic, smoldering mood disorder with a waxing and waning course 9 that can affect from 3% to 6% of the general population (life-time prevalence). 10,11 While some authors are skeptical about the effectiveness of antidepressants in the treatment of dysthymia, 12 others have reported much more favorable results. 13 As far as antidepressants are used extensively for treatment of dysthymia, the issue of the supposed loss of their effectiveness remains of great importance. The main goals of this chart-review study were: (i) to examine the rate of during antidepressants treatment of dysthymia; (ii) to compare the incidence of tolerance during SSRI and non-ssri trials; (iii) to give a descriptive analysis of the cases of. The relatively high rate of was supposed, especially for SSRI-treated patients. METHODS Subjects The detailed computerized files of the private outpatients treated between 2001 and 2010 were evaluated. Among all files (n = 1611), 142 cases (8.8%) diagnosed with dysthymia (according to DSM-IV criteria) were detected. The cases with full therapeutic response (clinical impression of complete remission or very minimal residual symptoms) for at least 3 consecutive months were selected. The additional inclusion criteria were: minimum of 6-month follow-up period with at least three follow-up meetings with the patient, a high level of patient cooperation and adherence to the treatment, no comorbid substance abuse, and severe personality disorders or prominent physical morbidity. Due to unclear data about total duration of illness and previous medication trials in some of the cases, this information was not included in the survey. Given the substantial overlap between anxiety and dysthymia, the differential diagnosis was not easy, but the patients with obvious and distinct anxiety disorders, such as obsessive compulsive disorder, panic attacks and post-traumatic stress disorder, were excluded from the study. Although the Rothschild Scale for Antidepressant Tachyphylaxis 4 was not used in complete form, was diagnosed based on the criteria of RSAT with the appearance of at least one of the following symptoms: apathy or decreased motivation, fatigue, dullness in cognitive function, sleep disturbance, weight gain, and sexual dysfunction for a minimum of 2 weeks after full response to antidepressants for a minimum of 3 consecutive months. As members of the Orthodox religious community, most of the patients included in the study were under traditional rabbis counseling, which included elements of cognitive behavioral therapy, supportive and directive psychotherapy. Data collection and analysis Computer-generated data were downloaded into Microsoft Excel workbooks. Routine sample descriptive statistics were applied to the demographic data. The c 2 statistic was used to examine the correlation between the two variables. RESULTS Out of 142 cases diagnosed with dysthymia, 52 patients (36.6%) met the criteria for response, length

3 Psychiatry and Clinical Neurosciences 2011; 65: Antidepressants for dysthymia 501 and frequency of follow up, adherence and lack of comorbidity; 28 (53.8%) were male and 24 were (46.2%) female. The majority of the examined patients (73%) were Orthodox Jews. Age varied from 18 to 79 years old; mean years. The length of follow up was from 6 to 86 months (mean ) with mean 4.4 meetings. In the studied group, 83 trials with different antidepressants were described: 74 trials were monotherapy and in nine trials the antidepressants were used in combination or with augmentation. In the cases of monotherapy, 48 trials were with different SSRI (escitalopram, fluoxetine, paroxetine, citalopram, sertraline), 14 trials were with serotonin norepinephrine reuptake inhibitors (SNRI) (duloxetine, venlafaxine, milnacipran), and four cases were with TCA (amitriptyline, clomipramine, maprotiline, imipramine). In eight trials, antidepressants with another mechanism of action (bupropion, mirtazapine, reboxetine) were chosen for the monotherapy. The SSRI were the first choice in 75 trials (90.3%); in eight trials, the SNRI or other medications were the first choice due to a history of side-effects or lack of effect of the SSRI. In nine trials with combined use of medications, the following combinations were prescribed. As a result of 58 antidepressant trials the full therapeutic responses for at least 3 consecutive months were achieved and these trials were defined as successful: 51 trials were monotherapy and seven trials were combined use. In 31 successful trials SSRI were used as monotherapy, SNRI were used in 12 trials, TCA were used in four trials and another antidepressant (mirtazapine) was used in four trials. In seven trials, response was achieved using combined therapy SSRI + TCA, bupropion + TCA and bupropion + lamotrigine. The cases of tolerance/ were observed in 12 patients (23% of patients) and in 13 trials (22.4% of trials). All cases of tolerance occurred during the monotherapy. The monotherapy trials of patients that finally fully responded were divided into two groups: SSRI trials and non-ssri trials (SNRI, TCA and other). Although the rate of successful trials in the non-ssri group was higher than that in the SSRI group (76.9.2% vs 64.6%) the difference was not statistically significant. The picture was quite dissimilar concerning the cases of : no cases were observed in the non- SSRI group while in the SSRI group in 13 cases (41.9.1% of successful trials), at some stage of the treatment was reported (c 2 = , P = ). The description of the cases of tolerance occurring in the patients, summarized in Table 1, shows great variability in the baseline demographic factors, time of appearance of tolerance, therapeutic strategies and results of treatment of the phenomena. DISCUSSION The results of the survey indicated the high possibility of developing tolerance to SSRI antidepressants during treatment of dysthymia. Although the elevated rate of tachyphylactic cases in SSRI-treated patients was hypothesized, the real frequency of the phenomena appeared to be surprisingly high with no such symptoms in the non-ssri group. Prominent differences between SSRI and other antidepressants concerning the issue of tolerance to medications in major depression were reported in some studies. In a retrospective study, Posternak and Zimmerman 7 compared rates of of TCA and venlafaxine, which act as dual reuptake inhibitors (though usually in high dosages) versus SSRI. The cohort reported having undergone 326 prior SSRI trials, 47 prior venlafaxine trials, and 35 prior trials with a TCA. Rates of were significantly lower with the dual reuptake inhibitors venlafaxine and TCA (3.7%) compared to rates of with SSRI (14.1%). Serotonin receptor desensitization has been hypothesized to be the primary actor responsible for the observation of an increased risk for the return of depressive symptoms during long-term treatment with selective serotonin reuptake inhibitors. 14 The data of higher frequency of poop out effect in SSRI medications compared to the dual reuptake inhibitors in the present study as well as in some others could be seen as an indirect support to this hypothesis. A multiphase, double-blind, placebo-controlled study assessed the efficacy of venlafaxine extended release (ER) during two sequential 1-year maintenance phases (A and B) in patients with recurrent major depressive disorder. 15 The maintenance phase A population was comprised of 337 patients (venlafaxine ER [n = 129], fluoxetine [n = 79], placebo [n = 129]), whereas 128 patients (venlafaxine ER [n = 43], fluoxetine [n = 45], placebo [n = 40]) were treated during maintenance phase B. No differences in the probability of experiencing were observed between the active treatment groups during either maintenance phase; however, only two medications from the SSRI and SNRI groups

4 502 G. Katz Psychiatry and Clinical Neurosciences 2011; 65: Table 1. Descriptive analysis of the cases of n Sex Age Time of follow up (months) Length of good response before appearance of (months) Medication possibly connected to Method of treating Results of treatment of 1 m Escitalopram 10 mg Increase dosage to 20 mg m Paroxetine 20 mg Increase dosage to 30 mg m Escitalopram 30 mg Decrease dosage to 20 mg ++ 4 m Escitalopram 10 mg Increase dosage to 15 mg f Escitalopram 20 mg Augmentation with +++ amitriptyline 25 mg 6 m first Escitalopram 10 mg Increase dosage to 20 mg +++ (temporary) 3-second Escitalopram 20 mg Shift to venlafaxine 225 mg m Escitalopram 20 mg Added cognitive behavioral +++ therapy 8 f Escitalopram 20 mg Augmentation with +++ clomipramine 50 mg 9 m Escitalopram 10 mg Increase dosage to 20 mg - Shift to bupropion 300 mg - Augmentation of bupropion + with amitriptyline 50 mg 10 f Escitalopram 20 mg Augmentation with maprotiline +/- 75 mg 11 m Escitalopram 20 mg Augmentation with imipramine mg 12 f Sertraline 100 mg Increase dosage to 200 mg - Shift to milnacipran 100 mg +++ (+++) full remission or very good response; (++) good response; (+) partial response; (+/-) questionable response; (-) no response. were compared and it is still unclear whether a follow up longer than 1 year would generate different results. The clinical aspects of the theory of as stepwise receptor desensitization during unipolar major depression were studied by Amsterdam and colleagues. 16 The results indicated that the number of prior antidepressant drug exposures was negatively associated with response to initial sertraline therapy and connected to stepwise receptor desensitization due to SSRI treatment. Interestingly, in the present study only one case of repetitive tolerance to different doses of escitalopram was described, which could be explained partly by the relatively low dosage (10 mg) of the medication used during the first stage of the treatment. Some research data indicate that the placebo effect might be of crucial importance in antidepressants influence in patients with mild or moderate symptoms. In the recently published meta-analysis by Fournier et al., 17 randomized placebo-controlled trials of antidepressants approved by the Food and Drug Administration in the treatment of major or minor depressive disorder were summarized. Conclusions of the study were that the magnitude of benefit of antidepressant medication compared with placebo increases with severity of depression symptoms and may be minimal or non-existent, on average, in patients with mild or moderate symptoms. Rather different results were reported in a meta-analysis concerning the antidepressant treatment of dysthymia. 18,19 Fifteen trials were included for the main comparisons. Similar results were obtained in terms of efficacy for different groups of drugs, such as TCA, SSRI, and monoamine oxidase inhibitors (MAOI). The pooled relative risk treatment response was 0.68 (95% CI ) for TCA, 0.64 (95% CI ) for SSRI, and 0.59 (95% CI ) for

5 Psychiatry and Clinical Neurosciences 2011; 65: Antidepressants for dysthymia 503 MAOI. There were no differences in response to active treatment when dysthymia was compared to dysthymia plus major depression or briefer non-major depressive states. The authors conclusion was that drug treatment appears to be effective in the shortterm management of dysthymic disorder. Although seen as a mild moderate kind of depressive disorder, dysthymia is quite different from lower-symptomlevel depressions in its chronic course; chronicity is known to be associated with poor response to placebo. 20 Therefore, it may be that the chronic nature of dysthymia explains the advantage of antidepressants over placebo in this condition. The data concerning the possible role of placebo in appearance of tolerance to antidepressants is sparse and contradictive. Some authors doubt the existence of true and attribute the loss of antidepressant response during most cases of maintenancephase therapy to either non-adherence and/or loss of placebo effect. 21,22 The problem of predisposition factors to is also far from clear. Summarizing mostly case reports and case series, Byrne and Rothschild 6 noted that most of the patients with reported were female; the mean age was years old, the average length of successful treatment before tolerance appearance was 24 weeks; the average length of remission was 12 weeks. Due to a relatively small absolute number of cases of and their heterogeneity in the present study, the issue of profiling of cases tolerance was rather difficult. The therapeutic attitudes towards the issue of are based more on common sense principles than on an evidence-based approach. In the survey about intervention in hypothetical cases of breakthrough depression in the patients taking different antidepressants, 23 the most popular choice was increasing the dosage, followed by augmenting with lithium or another antidepressant or changing to a different drug. In the present study the increasing dosage was the first (and most successful) choice for the overcoming of (see Table 1). The other tactics used were augmentation, usually of SSRI by TCA, and shift to another group of antidepressants (SNRI and Bupropion). Based on the assumption of the possibility of a therapeutic window for some SSRI, 24 in one case the tactic of lowering the dosage of escitalopram was successfully applied. Very few publications could be found concerning this method for the treatment of tolerance to SSRI. Cain 25 reported that in an open-label study, 23 consecutive outpatients were treated with fluoxetine 20 mg/day for major depression. Four of them failed to sustain initial improvements during 4 8 weeks of treatment (in the absence of apparent side-effects). All four patients responded to a lower dose. The author concluded that apparent difficulty in distinguishing fluoxetine s adverse effects/toxicity (or a therapeutic window effect) from underlying depressive symptoms exists; it may suggest the option of lowering the dose in some cases of non-response or tolerance. Although in most cases of the present survey the strategy of dosage change, switching and augmentation was successful, in the few other trials the results were less positive (see Table 1). Taking into consideration possible mutual mechanisms in their development, may contribute to the development of treatment-resistant depression. 26 The attitudes to the treatment of antidepressants may also involve non-medication strategies. Cognitive behavioral therapy treatment was added to escitalopram in one case of the discussed report with a positive outcome (Table 1). The possibility of promising results of this technique in the cases of SSRI tolerance was reported by Leykin et al., 27 who assessed the response to antidepressants therapy and cognitive therapy of patients with a history of prior antidepressant exposure. This observation suggests that cognitive therapy may exert its therapeutic action via a different mechanism than that of antidepressant drug therapy, and may be less affected by the physiological adaptation resulting from prior drug exposure. 28 Limitations As in all retrospective naturalistic chart review studies, this study has numerous and obvious methodological shortcomings. No structured rating scales and questionnaires were used in the evaluation of the patients. In addition, this study had special limitations: as was mentioned, most of the patients came from the Orthodox Jewish community with their specific cultural background and tendency to be treated by the same-sex therapist. As a result, the majority of the patients in the study were male, which does not represent the prevalence of dysthymia in the general population. The compared monotherapy groups were relatively small and the non-ssri group was heterogeneous in the mechanisms of action of medications. Tachyphylaxis was diagnosed mostly as exacerbation of different somatic features of depression

6 504 G. Katz Psychiatry and Clinical Neurosciences 2011; 65: with no clear affective signs. Therefore, there is overlap between those somatic symptoms of and the side-effects of SSRI, such as fatigue, weight gain, and sexual dysfunction. Although the side-effects of SSRI and are usually different at the time of appearance, the possibility of some misdiagnosing still exists. REFERENCES 1. Stedman s Medical Dictionary, 27th edn. Lippincott, Williams, and Wilkins, Philadelphia, PA, Solomon DA, Leon AC, Mueller TI et al. Tachyphylaxis in unipolar major depressive disorder. J. Clin. Psychiatry 2005; 66: Rothschild A. The Rothschild scale for antidepressant. Poster presented at: 159th Annual Meeting of the American Psychiatric Association; May 20 25, 2006; Toronto, Canada. 4. Rothschild A. The Rothschild scale for antidepressant : reliability and validity. Compr. Psychiatry 2008; 49: Katz G. Tachyphylaxis /tolerance to the antidepressive medications: a review. Isr. J. Psychiatry 2010 (in press). 6. Byrne S, Rothschild A. Loss of antidepressant efficacy during maintenance therapy: possible mechanisms and treatments. J. Clin. Psychiatry 1998; 59: Posternak MA, Zimmerman M. Dual reuptake inhibitors incur lower rates of than selective serotonin reuptake inhibitors: a retrospective study. J. Clin. Psychiatry 2005; 66: American Psychiatric Association. The Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Text Revision. American Psychiatric Press, Inc, Washington, DC, Sansone RA, Sansone LA. Dysthymic disorder: forlorn and overlooked? Psychiatry (Edgmont) 2009; 6: Weissman MM, Leaf PJ, Bruce ML, Florio L. The epidemiology of dysthymia in five communities: rates, risks, comorbidity, and treatment. Am. J. Psychiatry 1988; 145: Wittchen HU, Knäuper B, Kessler RC. Lifetime risk of depression. Br. J. Psychiatry Suppl. 1994; 26: Ghaemi SN. Why antidepressants are not antidepressants: STEP-BD, STAR*D, and the return of neurotic depression. Bipolar Disord. 2008; 10: Cuijpers P, van Straten A, Schuurmans J, van Oppen P, Hollon SD, Andersson G. Psychotherapy for chronic major depression and dysthymia: a meta-analysis. Clin. Psychol. Rev. 2010; 30: Cornelisse LN, Van der Harst JE, Lodder JC et al. Reduced 5-HT1A- and GABAB receptor function in dorsal raphé neurons upon chronic fluoxetine treatment of socially stressed rats. J. Neurophysiol. 2007; 98: Rothschild AJ, Dunlop BW, Dunner DL et al. Assessing Rates and Predictors of Tachyphylaxis During the Prevention of Recurrent Episodes of Depression With Venlafaxine ER for Two Years (PREVENT) Study. Psychopharmacol. Bull. 2009; 42: Amsterdam J, Williams D, Michelson D et al. Tachyphylaxis after repeated antidepressant drug exposure in patients with recurrent major depressive disorder. Neuropsychobiology 2009; 59: Fournier JC, DeRubeis RJ, Hollon SD et al. Antidepressant drug effects and depression severity: a patient-level metaanalysis. JAMA 2010; 303: de Lima MS, Hotoph M, Wessely S. The efficacy of drug treatments for dysthymia: a systematic review and metaanalysis. Psychol. Med. 1999; 6: Lima MS, Moncrieff J. Drugs versus placebo for dysthymia. Cochrane Database Syst. Rev. 2000; (4): CD Dunner DL. Acute and maintenance treatment of chronic depression. J. Clin. Psychiatry 2001; 62 (Suppl. 6): Zimmerman M, Thongy T. How often do SSRIs and other new-generation antidepressants lose their effect during continuation treatment? Evidence suggesting the rate of true during continuation treatment is low. J. Clin. Psychiatry 2007; 68: Thase MA. Preventing relapse and recurrence of depression: a brief review of therapeutic options. CNS Spectr. 2006; 11: Byrne S, Rothschild AJ. Psychiatrists responses to failure of maintenance therapy with antidepressants. Psychiatr Serv. 1997; 48: Fichtner CG, Jobe TH, Braun BG. Possible therapeutic window for serotonin reuptake inhibitors. J. Clin. Psychiatry 1994; 55: Cain JW. Poor response to fluoxetine: underlying depression, serotonergic overstimulation, or a therapeutic window? J. Clin. Psychiatry 1992; 53: Fekadu A, Wooderson SC, Markopoulo K, Donaldson C, Papadopoulos A, Cleare AJ. What happens to patients with treatment-resistant depression? A systematic review of medium to long term outcome studies. J. Affect. Disord. 2009; 116: Leykin Y, Amsterdam JD, DeRubeis RJ, Gallop R, Shelton RC, Hollon SD. Progressive resistance to a selective serotonin reuptake inhibitor but not to cognitive therapy in the treatment of major depression. J. Consult. Clin. Psychol. 2007; 75: Amsterdam J, Shultz J. Does occur after repeated antidepressant exposure in patients with Bipolar II major depressive episode? J. Affect. Disord. 2009; 115: